tbuckley/cabot-search huggingface dataset:
RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease
Authors: Marta B. Afonso, Tawhidul Islam, Julie Magusto, Ricardo Amorim, Véronique Lenoir, Rui F. Simões, José Teixeira, Liana C. Silva, Dominique Wendum, Isabelle Jéru, Corinne Vigouroux, Rui E. Castro, Paulo J. Oliveira, Carina Prip‐Buus, Vlad Ratziu, Jérémie Gautheron, Cecília M. P. Rodrigues
Journal: Hepatology (2022)

Background and Aims: Receptor‐interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD. Approach and Results: Functional studies evaluating mitochondria and LD biology were performed in wild‐type (WT) and Ripk3 −/− mice fed a choline‐deficient, amino acid‐defined (CDAA) diet for 32 and 66 weeks and in CRISPR‐Cas9 Ripk3 ‐null fat‐loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1 ‐associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet–fed mice and fat‐loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3 −/− hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD‐associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3 −/− hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy. Conclusions: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.
The application of zebrafish patient‐derived xenograft tumor models in the development of antitumor agents
Authors: Xiang Li, Minyong Li
Journal: Medicinal Research Reviews (2022)

Abstract The cost of antitumor drug development is enormous, yet the clinical outcomes are less than satisfactory. Therefore, it is of great importance to develop effective drug screening methods that enable accurate, rapid, and high‐throughput discovery of lead compounds in the process of preclinical antitumor drug research. An effective solution is to use the patient‐derived xenograft (PDX) tumor animal models, which are applicable for the elucidation of tumor pathogenesis and the preclinical testing of novel antitumor compounds. As a promising screening model organism, zebrafish has been widely applied in the construction of the PDX tumor model and the discovery of antineoplastic agents. Herein, we systematically survey the recent cutting‐edge advances in zebrafish PDX models (zPDX) for studies of pathogenesis mechanisms and drug screening. In addition, the techniques used in the construction of zPDX are summarized. The advantages and limitations of the zPDX are also discussed in detail. Finally, the prospects of zPDX in drug discovery, translational medicine, and clinical precision medicine treatment are well presented.
Neural Tube Defects
Authors: Ronald J. Lemire
Journal: JAMA (1988)

Neural tube defects (NTDs) are a group of malformations of the brain and spinal cord that originate at various times during gestation. The most common NTDs are anencephaly and meningomyelocele, which arise during the process of neurulation, a well-defined period between the 17th and 30th day after ovulation. These NTDs are clinically apparent by being open, ie, leaving nervous tissue exposed, in contrast to postneurulation NTDs that are skin covered. The incidence of NTDs is declining in several areas of the world, including the United States. While the reasons for this are unclear, there seems to be some effect from prenatal diagnosis, genetic counseling, and possibly nutritional supplementation. (<i>JAMA</i>1988;259:558-562)
Spatial Positioning and Matrix Programs of Cancer-Associated Fibroblasts Promote T-cell Exclusion in Human Lung Tumors
Authors: John A. Grout, Philemon Sirven, Andrew M. Leader, Shrisha Maskey, Eglantine Hector, Isabelle Puisieux, Fiona Steffan, Evan Cheng, Navpreet Tung, Mathieu Maurin, Romain Vaineau, Lea Karpf, Martin Plaud, Anne-Laure Begue, Koushik Ganesh, Jérémy Mesple, Maria Casanova-Acebes, Alexandra Tabachnikova, Shilpa Keerthivasan, Alona Lansky, Jessica Le Berichel, Laura Walker, Adeeb H. Rahman, Sacha Gnjatic, Nicolas Girard, Marine Lefevre, Diane Damotte, Julien Adam, Jerome C. Martin, Andrea Wolf, Raja M. Flores, Mary Beth Beasley, Rachana Pradhan, Soren Muller, Thomas U. Marron, Shannon J. Turley, Miriam Merad, Ephraim Kenigsberg, Hélène Salmon
Journal: Cancer Discovery (2022)

Abstract It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which are associated with T-cell exclusion: (i) MYH11+αSMA+ CAF, which are present in early-stage tumors and form a single cell layer lining cancer aggregates, and (ii) FAP+αSMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both populations orchestrate a particular structural tissue organization through dense and aligned fiber deposition compared with T cell–permissive CAF. Yet they produce distinct matrix molecules, including collagen IV (MYH11+αSMA+ CAF) and collagen XI/XII (FAP+αSMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T-cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell–excluded tumors. Significance: The cellular and molecular programs driving T-cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T-cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to developing new strategies targeting T cell–excluding CAF. See related commentary by Sherman, p. 2501. This article is highlighted in the In This Issue feature, p. 2483
2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction
Authors: Patrick T. O'Gara, Frederick G. Kushner, Deborah D. Ascheim, Donald E. Casey, Mina K. Chung, James A. de Lemos, Steven M. Ettinger, James C. Fang, Francis M. Fesmire, Barry A. Franklin, Christopher B. Granger, Harlan M. Krumholz, Jane A. Linderbaum, David A. Morrow, L. Kristin Newby, Joseph P. Ornato, Narith Ou, Martha J. Radford, Jacqueline E. Tamis-Holland, Carl L. Tommaso, Cynthia M. Tracy, Y. Joseph Woo, David X. Zhao
Journal: Journal of the American College of Cardiology (2012)
Increased Lung Immune Metabolic Activity in COVID-19 Survivors
Authors: Rosana Souza Rodrigues, Gabriel Motta Ribeiro, Miriam Menna Barreto, Walter Araujo Zin, Júlia de Toledo-Mendes, Philippe Alcantara G. Martins, Sergio Altino de Almeida, Rodrigo Basílio, Remy Martins-Gonçalves, Eugênio Damaceno Hottz, Patricia T. Bozza, Fernando A. Bozza, Alysson Roncally Silva Carvalho, Paulo Henrique Rosado-de-Castro
Journal: Clinical Nuclear Medicine (2022)

We quantified lung glycolytic metabolic activity, clinical symptoms and inflammation, coagulation, and endothelial activation biomarkers in 2019 coronavirus disease (COVID-19) pneumonia survivors.Adults previously hospitalized with moderate to severe COVID-19 pneumonia were prospectively included. Subjects filled out a questionnaire on clinical consequences, underwent chest CT and 18 F-FDG PET/CT, and provided blood samples on the same day. Forty-five volunteers served as control subjects. Analysis of CT images and quantitative voxel-based analysis of PET/CT images were performed for both groups. 18 F-FDG uptake in the whole-lung volume and in high- and low-attenuation areas was calculated and normalized to liver values. Quantification of plasma markers of inflammation (interleukin 6), d -dimer, and endothelial cell activation (angiopoietins 1 and 2, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1) was also performed.We enrolled 53 COVID-19 survivors (62.3% were male; median age, 50 years). All survivors reported at least 1 persistent symptom, and 41.5% reported more than 6 symptoms. The mean lung density was greater in survivors than in control subjects, and more metabolic activity was observed in normal and dense lung areas, even months after symptom onset. Plasma proinflammatory, coagulation, and endothelial activation biomarker concentrations were also significantly higher in survivors.We observed more metabolic activity in areas of high and normal lung attenuation several months after moderate to severe COVID-19 pneumonia. In addition, plasma markers of thromboinflammation and endothelial activation persisted. These findings may have implications for our understanding of the in vivo pathogenesis and long-lasting effects of COVID-19 pneumonia.
Concordance of SARS-CoV-2 Results in Self-collected Nasal Swabs vs Swabs Collected by Health Care Workers in Children and Adolescents
Authors: Jesse J. Waggoner, Miriam B. Vos, Erika A. Tyburski, Phuong-Vi Nguyen, Jessica M. Ingersoll, Candace Miller, Julie Sullivan, Mark Griffiths, Cheryl Stone, Macarthur Benoit, Laura Benedit, Brooke Seitter, Robert Jerris, Joshua M. Levy, Colleen S. Kraft, Sarah Farmer, Amanda Peagler, Anna Wood, Adrianna L. Westbrook, Claudia R. Morris, Usha N. Sathian, William Heetderks, Li Li, Kristian Roth, Mary Barcus, Timothy Stenzel, Greg S. Martin, Wilbur A. Lam
Journal: JAMA (2022)

<h3>Importance</h3> Despite the expansion of SARS-CoV-2 testing, available tests have not received Emergency Use Authorization for performance with self-collected anterior nares (nasal) swabs from children younger than 14 years because the effect of pediatric self-swabbing on SARS-CoV-2 test sensitivity is unknown. <h3>Objective</h3> To characterize the ability of school-aged children to self-collect nasal swabs for SARS-CoV-2 testing compared with collection by health care workers. <h3>Design, Setting, and Participants</h3> Cross-sectional study of 197 symptomatic children and adolescents aged 4 to 14 years old. Individuals were recruited based on results of testing in the Children’s Healthcare of Atlanta system from July to August 2021. <h3>Exposures</h3> Children and adolescents were given instructional material consisting of a short instructional video and a handout with written and visual steps for self-swab collection. Participants first provided a self-collected nasal swab. Health care workers then collected a second specimen. <h3>Main Outcomes and Measures</h3> The primary outcome was SARS-CoV-2 detection and relative quantitation by cycle threshold (Ct) in self- vs health care worker–collected nasal swabs when tested with a real-time reverse transcriptase–polymerase chain reaction test with Emergency Use Authorization. <h3>Results</h3> Among the study participants, 108 of 194 (55.7%) were male and the median age was 9 years (IQR, 6-11). Of the 196 participants, 87 (44.4%) tested positive for SARS-CoV-2 and 105 (53.6%) tested negative by both self- and health care worker–collected swabs. Two children tested positive by self- or health care worker–collected swab alone; 1 child had an invalid health care worker swab. Compared with health care worker–collected swabs, self-collected swabs had 97.8% (95% CI, 94.7%-100.0%) and 98.1% (95% CI, 95.6%-100.0%) positive and negative percent agreement, respectively, and SARS-CoV-2 Ct values did not differ significantly between groups (mean [SD] Ct, self-swab: 26.7 [5.4] vs health care worker swab: 26.3 [6.0];<i>P</i> = .65). <h3>Conclusions and Relevance</h3> After hearing and seeing simple instructional materials, children and adolescents aged 4 to 14 years self-collected nasal swabs that closely agreed on SARS-CoV-2 detection with swabs collected by health care workers.
Potential Pitfall of Fluciclovine PET/CT in Castrate-Resistant Prostate Cancer With Adrenal Metastasis
Authors: Jin Qi, Nghi C. Nguyen
Journal: Clinical Nuclear Medicine (2022)

Abstract An 83-year-old man with castrate-resistant prostate cancer underwent an 18 F-fluciclovine PET/CT scan, which was negative for local disease recurrence or locoregional lymphadenopathy, but there were multiple fluciclovine-avid bone metastases. In addition, mildly avid bilateral adrenal nodules were thought to be benign. However, on follow-up PET/CT 10 months later, while on additional therapy with enzalutamide, the bilateral nodules became mass lesions with interval decreased fluciclovine avidity. Adrenal metastases were suspected given their rapid growth, with subsequent CT-guided biopsy revealing metastatic prostate cancer without tumor necrosis. This false-negative case highlights the diagnostic challenge of fluciclovine PET in characterizing adrenal lesions.
Intense 68Ga-Pentixafor Activity in Idiopathic Retroperitoneal Fibrosis
Authors: Qiaoqiao Shu, Mei Hu, Maoxue Deng, Yue Chen, Liang Cai
Journal: Clinical Nuclear Medicine (2022)

Abstract A 52-year-old man was admitted to our hospital with lower abdominal and low back pain, and abdomen CT at an outside hospital presented a retroperitoneal mass with left urinary tract obstruction and hydronephrosis. In 68 Ga-pentixafor PET/CT, the retroperitoneal mass showed intense radioactivity. Subsequently, the patient underwent biopsy of the retroperitoneal mass. The pathological examination showed only fibrous tissue without tumor cells. The patient was finally diagnosed with idiopathic retroperitoneal fibrosis. Our case demonstrated that idiopathic retroperitoneal fibrosis had intense uptake of 68 Ga-pentixafor.
Physiology‐Inspired Multilayer Nanofibrous Membranes Modulating Endogenous Stem Cell Recruitment and Osteo‐Differentiation for Staged Bone Regeneration
Authors: Yingji Mao, Yu Chen, Weifeng Li, Ying Wang, Jingjing Qiu, Yingxiao Fu, Jianzhong Guan, Pinghui Zhou
Journal: Advanced Healthcare Materials (2022)

Abstract Bone regeneration involves a cascade of sophisticated, multiple‐staged cellular and molecular events, where early‐phase stem cell recruitment mediated by chemokines and late‐phase osteo‐differentiation induced by pro‐osteogenic factors play the crucial roles. Herein, enlightened by a bone physiological and regenerative mechanism, the multilayer nanofibrous membranes (PLLA@SDF‐1 α @MT01) consisting of PLLA/MT01 micro‐sol electrospun nanofibers as intima and PLLA/PEG/SDF‐1 α electrospun nanofibers as adventitia are fabricated through micro‐sol electrospinning and manual multi‐layer stacking technologies. In vitro releasing profiles show that PLLA@SDF‐1 α @MT01 represents the rapid release of stromal cell‐derived SDF‐1 α (SDF‐1 α ) in the outer layers, while with long‐term sustained release of MT01 in the inner layer. Owing to interconnected porosity like the natural bone extracellular matrix and improved hydrophilia, PLLA@SDF‐1 α @MT01 manifests good biocompatibility both in vitro and in vivo. Furthermore, PLLA@SDF‐1 α @MT01 can promote bone marrow mesenchymal stem cells (BMSCs) migration by amplifying the SDF‐1 α /CXCR4 axis and stimulating BMSCs osteo‐differentiation via activating the MAPK pathway in vitro. PLLA@SDF‐1 α @MT01, with a programmed dual‐delivery system, exhibits the synergetic promotion of bone regeneration and vascularization by emulating key characteristics of the staged bone repair in vivo. Overall, PLLA@SDF‐1 α @MT01 that mimics the endogenous cascades of bone regeneration can enrich the physiology‐mimetic staged regenerative strategy and represent a promising tissue‐engineered scaffold for the bone defect.
Biomimetic Dp44mT-nanoparticles selectively induce apoptosis in Cu-loaded glioblastoma resulting in potent growth inhibition
Authors: Muhammad Ismail, Wen Yang, Yanfei Li, Yibin Wang, Wenya He, Jiefei Wang, Pir Muhammad, Timothy B. Chaston, Fawad Ur Rehman, Meng Zheng, David B. Lovejoy, Bingyang Shi
Journal: Biomaterials (2022)
Smartphone-based screening for atrial fibrillation: a pragmatic randomized clinical trial
Authors: Konstantinos D. Rizas, Luisa Freyer, Nikolay Sappler, Lukas von Stülpnagel, Peter Spielbichler, Aresa Krasniqi, Michael Schreinlechner, Felix N. Wenner, Fabian Theurl, Amira Behroz, Elodie Eiffener, Mathias P. Klemm, Annika Schneidewind, Martin Zens, Theresa Dolejsi, Ulrich Mansmann, Steffen Massberg, Axel Bauer
Journal: Nature Medicine (2022)
Efficacy of pp65‐specific <scp>TCR‐T</scp> cell therapy in treating cytomegalovirus infection after hematopoietic stem cell transplantation
Authors: Guangna Liu, Hua Chen, Xingyu Cao, Lemei Jia, Wei Rui, Hongli Zheng, Daosheng Huang, Fang Liu, Yue Liu, Xueqiang Zhao, Peihua Lu, Xin Lin
Journal: American Journal of Hematology (2022)

Abstract Cytomegalovirus (CMV) infection remains a major cause of mortality after hematopoietic stem cell transplantation (HSCT). Current treatments, including antiviral drugs and adoptive cell therapy with CMV‐specific cytotoxic T lymphocytes (CTLs), only show limited benefits in patients. T‐cell receptor (TCR)‐T cell therapy offers a promising option to treat CMV infections. Here, using tetramer‐based screening and single‐cell TCR cloning technologies, we identified various CMV antigen‐specific TCRs from healthy donors, and generated TCR‐T cells targeting multiple pp65 epitopes corresponding to three major HLA‐A alleles. The TCR‐T cells showed efficient cytotoxicity toward epitope‐expressing target cells in vitro. After transfer into immune‐deficient mice bearing pp65 + HLA + tumor cells, TCR‐T cells induced dramatic tumor regression and exhibited long‐term persistence. In a phase I clinical trial (NCT04153279), CMV TCR‐T cells were applied to treat patients with CMV reactivation after HSCT. Except one patient who withdrew at early treatment stage, all other six patients were well‐tolerated and achieved complete response (CR), no more than grade 2 cytokine release syndrome (CRS) and other adverse events were observed. CMV TCR‐T cells persisted up to 3 months. Among them, two patients have survived for more than 1 year. This study demonstrates the great potential in the treatment and prevention of CMV infection following HSCT or other organ transplantation.
Hospital Admissions for Abdominal Pain in Childhood
Authors: R B Crossley
Journal: Journal of the Royal Society of Medicine (1982)

From January to March 1980, a consecutive sample of 50 children admitted to hospital with acute abdominal pain provisionally diagnosed as appendicitis but who recovered spontaneously without a specific physical diagnosis was studied. The instruments used were a standardized parental interview and Rutter A(2) and B(2) questionnaires which are designed as screening devices to explore levels of emotional adjustment in children. A comparison was made with 43 children (controls) matched for sex and age from the same schools. Forty children suffering from acute appendicitis were studied in the same way. A significantly increased number of children in the nonspecific group obtained abnormal scores on the Rutter Scales compared with the control group ( P &lt; 0.025). An unexpectedly large number (31%) of boys suffering from acute appendicitis obtained abnormal scores on the Rutter Scales. Postal follow up three months following discharge from hospital indicated that 8 (16%) of the nonspecific group were incapacitated to the extent of missing school. During the study, 15 children had a normal appendix removed at operation. Seven of them showed a significant degree of maladjustment.
Spatial patterning of phenotypically distinct microtissues to engineer osteochondral grafts for biological joint resurfacing
Authors: Ross Burdis, Farhad Chariyev-Prinz, David C. Browe, Fiona E. Freeman, Jessica Nulty, Emily E. McDonnell, Kian F. Eichholz, Bin Wang, Pieter Brama, Daniel J. Kelly
Journal: Biomaterials (2022)

Modular biofabrication strategies using microtissues or organoids as biological building blocks have great potential for engineering replacement tissues and organs at scale. Here we describe the development of a biofabrication strategy to engineer osteochondral tissues by spatially localising phenotypically distinct cartilage microtissues within an instructive 3D printed polymer framework. We first demonstrate that immature cartilage microtissues can spontaneously fuse to form homogeneous macrotissues, and that combining less cellular microtissues results in superior fusion and the generation of a more hyaline-like cartilage containing higher levels of sulphated glycosaminoglycans and type II collagen. Furthermore, temporally exposing developing microtissues to transforming growth factor-β accelerates their volumetric growth and subsequent capacity to fuse into larger hyaline cartilage grafts. Next, 3D printed polymeric frameworks are used to further guide microtissue fusion and the subsequent self-organisation process, resulting in the development of a macroscale tissue with zonal collagen organisation analogous to the structure seen in native articular cartilage. To engineer osteochondral grafts, hypertrophic cartilage microtissues are engineered as bone precursor tissues and spatially localised below phenotypically stable cartilage microtissues. Implantation of these engineered grafts into critically-sized caprine osteochondral defects results in effective defect stabilisation and histologically supports the restoration of a more normal articular surface after 6 months in vivo. These findings support the use of such modular biofabrication strategies for biological joint resurfacing.
Clinical impact of next-generation sequencing on laboratory diagnosis of suspected culture-negative meningitis and encephalitis
Authors: Fanfan Xing, Qingyan Yang, Chaowen Deng, Linlin Sun, Zhendong Luo, Haiyan Ye, Jin Yang, Simon K F Lo, Susanna K P Lau, Patrick C Y Woo
Journal: Journal of Infection (2022)
Possibilities and promise: Leveraging advances in transcriptomics for clinical decision making in allergic diseases
Authors: Camille M Moore, Max A Seibold
Journal: Journal of Allergy and Clinical Immunology (2022)

Transcriptomics has revolutionized our understanding of the pathobiologic heterogeneity underlying complex allergic diseases, leading to both the discovery of multiple inflammatory allergic disease endotypes and the development of targeted biologic therapies. In addition, transcriptomic endotypes have been associated with disease severity, exacerbation propensity, and responsiveness to nontargeted therapies, suggesting an unrealized potential for transcriptomic assays and endotyping to be used as diagnostic, predictive, and prognostic biomarkers. In this review, we discuss current and emerging transcriptomic technologies and how they have been used to uncover allergic disease endotypes and generate other clinically relevant findings. We then discuss how transcriptomics could be leveraged in the clinic for the delivery of personalized, rational patient care, and we consider strategies for and impediments to their future clinical deployment.
Giant congenital melanocytic naevus with a novel <i>CUX1–BRAF</i> fusion mutation treated with trametinib
Authors: Vered Molho-Pessach, Stav Hartshtark, Sharon Merims, Michal Lotem, Nadia Caplan, Hila Alfassi, Alex Maly, Gal Goldstein, Rakefet Sidlik Muskatel
Journal: British Journal of Dermatology (2022)